Project Summary The epicardium has several critical functions during midgestation mouse heart development. The continuing focus of this project is to understand these processes individually and to integrate their developmental and regulatory logic with each other, with other aspects of heart development, and with the larger context of overall embryo development In Aim 1, we consider the function of epicardial mitogenic signaling that induces cardiomyocyte proliferation, and in particular address the nature of regulation of mitogen expression in the pre- and post-placental period of midgestation development. A primary goal is to confirm how ventricular chamber growth is coordinated with placental function. Our recent work established that CXCL12 is required for coronary vasculogenesis. Taking advantage of the unique features of CXCL12 as an organ-specific, arterial-specific, and paracrine-acting vascular maturation factor, in Aim 2 we propose several experimental strategies to better define the process of coronary plexus maturation, to resolve the source of coronary arterial endothelium based on requirement for CXCL12 signaling, and to develop a novel strategy to visualize the process of venous to arterial reprogramming. Although cardiomyocyte proliferation and coronary vasculogenesis are completed by birth, both are reactivated in the neonatal mouse heart after injury. In Aim 3, we examine how the same signals that support these processes in midgestation heart morphogenesis are reutilized in the neonatal heart for regeneration.